Download Microbiota and neurodevelopmental windows: implications for brain

TRMOME-955; No. of Pages 10
Review
Microbiota and neurodevelopmental
windows: implications for brain
disorders
Yuliya E. Borre1, Gerard W. O’Keeffe2,3, Gerard Clarke1,4, Catherine Stanton4,5,
Timothy G. Dinan1,4, and John F. Cryan1,2
1
Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
3
The Irish Centre for Fetal and Neonatal Translational Research (INFANT), Cork University Maternity Hospital, Cork, Ireland
4
Department of Psychiatry, University College Cork, Cork, Ireland
5
Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland
2
Gut microbiota is essential to human health, playing a
major role in the bidirectional communication between
the gastrointestinal tract and the central nervous system. The microbiota undergoes a vigorous process of
development throughout the lifespan and establishes its
symbiotic rapport with the host early in life. Early life
perturbations of the developing gut microbiota can impact neurodevelopment and potentially lead to adverse
mental health outcomes later in life. This review compares the parallel early development of the intestinal
microbiota and the nervous system. The concept of
parallel and interacting microbial–neural critical windows opens new avenues for developing novel microbiota-modulating based therapeutic interventions in
early life to combat neurodevelopmental deficits and
brain disorders.
Microbiota–gut–brain axis
Microbes within and on our bodies are a thriving dynamic
population forming a symbiotic superorganism. The collective comprises a myriad of bacteria, of approximately 1014
cells, containing 100 times the number of genes of the
human genome [1]. Despite the evolution of this microbiome (see Glossary) for 500 million years [2,3], it is only
recently that advances in sequencing technology have
allowed us to appreciate the full nature of the complexities
of host–microbe relationships. The largest microbial component of the human microbiome is located in the large
intestine of the gastrointestinal (GI) tract. It is now clear
that the gut microbiota plays a key role in the life and
health of the host by protecting against pathogens, metabolizing dietary nutrients and drugs, and influencing the
absorption and distribution of dietary fat [2]. However,
the influence of the microbiota extends beyond the GI tract,
playing a major role in the bidirectional communication
Corresponding author: Cryan, J.F. ([email protected]).
Keywords: brain–gut axis; stress; neurogastroenterology; microbiome; brain disorders; autism.
1471-4914/
ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2014.05.002
Glossary
Alzheimer’s disease: a progressive age-associated neurodegenerative disorder
characterized by cognitive decline and build-up of protein ‘plaques’ and
‘tangles’ in the brain.
Astrocytes: the most abundant glial cell of the human brain, providing
support for the blood–brain barrier, provision of nutrients to the nervous
tissue, and a role in the repair and scarring process of the CNS following
traumatic injuries.
Attention deficity hyperactivity disorder (ADHD): a psychiatric disorder usually
occurring in childhood characterized by significant attention problems,
hyperactivity, or impulsivity.
Autism: a neurodevelopmental disorder characterized by the presence of
stereotypical behavior and communication and social interaction deficits, with
a male gender bias.
Brain–gut axis: a complex network of communication between the gut and the
brain, which modulates the GI tract and CNS, playing an important role in
maintaining homeostasis.
Cortical neurogenesis: the generation of new neurons in the cerebral cortex.
Dysbiosis: a microbial imbalance on or within the body, often localized to the
gut.
Gliogenesis: the generation of new glial cells.
Irritable bowel syndrome: a disorder of the brain–gut axis. In addition to GI
symptoms, irritable bowel syndrome is also associated with frequent
comorbidities of depression and anxiety.
Hippocampal neurogenesis: a process by which neurons are generated in the
hippocampus.
Leaky gut: an increase in the permeability of the intestinal mucosa, allowing
bacteria and toxins to leak into the bloodstream (Box 2).
Microbiome: the collective genomes of all the microorganisms in a microbiota.
Microbiota: the entire microbial population residing in particular parts of the
body, such as the intestine or skin.
Mood disorders: a constellation of mental disorders encompassing major
depression and bipolar disorder (combining episodes of both mania and
depression).
Neurodevelopment: the development of the CNS system, occurring mostly in
prenatal and early life.
Neurulation: a key neurodevelopmental event that begins the genesis of the
nervous system by ‘folding’ the embryonic nervous system to form the neural
tube.
Schizophrenia: a mental disorder characterized by positive (hallucinations and
delusions) and negative (anhedonia, social withdrawal) symptoms, which
typically emerge in adolescence and early adulthood.
Short chain fatty acids (SCFAs): bacterial products or metabolites from the
fermentation of dietary carbohydrates in the gut, which have immunomodulatory properties and can interact with nerve cells by stimulating the
sympathetic nervous system.
Synaptic pruning: a process where synapses are eliminated during neurodevelopment and/or aging.
Systems matching: a process that refines neuronal numbers to match the
requirements of the neural circuit which they become part of.
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Healthy CNS
Stress and disease
→ Abnormal behavior and cognion, stress, visceral pain
Macrophage
Homeosatac
signals
Intesnal
epithelial
barrier
Symbiosis/diverse microbiota:
intesnal barrier integrity maintained,
pathobionts are kept in check
Gut dysfuncon
Healthy Gut
Key:
Dysbiosis: pathobiont overgrowth,
promong loss of intesnal barrier
(leaky gut)
Pathobionts
Symbionts
SCFAs
Neurotransmier
Proinflammatory cytokines
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Figure 1. Microbiota–gut–brain axis communication in health and disease. (Left) Under healthy conditions, the predominance of symbiotic bacteria, an intact intestinal
barrier, a healthy innate immunity controlling pathobiont overgrowth inside the intestinal tract and healthy gut function support the symbiotic relationship between CNS
function and gut microbiota. (Right) Under pathological stress and/or disease conditions, intestinal dysbiosis can adversely influence gut physiology leading to
inappropriate brain–gut axis signaling and associated consequences for CNS functions and disease states. Stress at the level of the CNS can also impact on gut function and
lead to perturbations of the microbiota. A change in the balance of symbionts and pathobionts favoring pathobiont overgrowth results in dysbiosis, which can induce
inflammation. During inflammatory responses, macrophages contribute to pathogenesis through inappropriate responses to enteric microbial stimuli, inefficient clearance
of microbes from host tissues, and impaired proinflammatory and anti-inflammatory responses, and loss of barrier function (leaky gut; see Box 2). This promotes the
increased translocation of pathogenic bacterial components from the intestinal mucosa to the systemic circulation, where they activate innate immunity, characterized by
production of proinflammatory cytokines, resulting in systemic inflammation and abnormal gut function. These mechanisms potentially lead to impaired CNS function
such as altered neurochemistry, cognition, behavior, stress response, and visceral pain. Abbreviations: CNS, central nervous system; SCFAs, short chain fatty acids.
between the GI tract and the central nervous system (CNS)
[4] (Figure 1).
The concept of the brain–gut axis emerged in the 19th and
early 20th centuries from the pioneering observations of
Beaumont, Darwin, and Cannon in tandem with the now
classical physiological studies of Ivan Pavlov [4,5]. More
recently, given the realization of the importance of the
microbiota in modulating health, the brain–gut axis has
been extended to the microbiota–gut–brain axis [6–8], which
represents a complex network of communication between
the gut, the intestinal microbiota, and the brain, modulating
immune, GI, and CNS functions [6,9]. It encompasses the
CNS, the sympathetic and parasympathetic branches of the
autonomic nervous system, as well as the enteric nervous
system and the neuroendocrine and neuroimmune systems
[10]. In healthy individuals, the normal dominant microbiota is relatively stable and forms a mutually beneficial
rapport with the host. However, perturbations in the delicate synergetic host–microbiota relationship may have serious consequences and has the potential to exacerbate
brain, digestive, and metabolic disorders [9–14]
(Figure 1). For example, bidirectional communication between the microbiota and the CNS influences stress reactivity, pain perception, neurochemistry, and several brain–
gut axis disorders [4,7,15]. Despite several investigations
focusing on the exploration of the bidirectional communication between the microbiota and the CNS, more is known
about gut microbiota modifying CNS (Box 1), whereas the
mechanisms by which the CNS can modify gut microbial
communities remain to be fully elucidated.
In addition to neural, endocrine, and metabolic pathways, immunological mechanisms may be an additional
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mechanism in signaling with the potential to affect neurodevelopment. Leaky gut (Figure 1 and Box 2) as the
result of dysbiosis offers an alternative mechanism of
inducing an immune response, and the phenotypic changes
of immune cells induced by gut microbes may modulate the
neurodevelopment–microbiota interaction.
The dynamics of the various endogenous and exogenous
factors, which may have a profound effect on the microbiota
composition leading to dysbiosis and impacting multiple
human pathologies, from metabolic syndromes to mental
disorders are slowly being unraveled [16]. The microbiota
undergoes a vigorous process of maturation and development throughout lifespan and establishes its mutually
beneficial cohabitation with the host during life. The composition of the gut microbiota during critical periods of
CNS development is affected by a broad range of factors.
Perturbation of any of these factors can lead to host stress
or disease (Figure 1).
Shaping of the microbiota occurs in parallel with neurodevelopment and they have similar critical developmental windows (Figure 2) sensitive to damage. Recently, the
microbiota–gut–brain axis emerged as a key player in
neurodevelopmental phases, indicating that early-life
events during initial colonization and microbiota development can determine general and mental health in later life
[17,18]. Importantly, childhood and adolescence are the
most dynamic periods of change in relation to microbiota
and brain development. Thus, disruptions during such
critical periods of dynamic microbiota–host interaction
have the potential to profoundly alter brain–gut signaling,
affect health throughout life, and increase the risk of (or
lead to) neurodevelopmental disorders.
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Box 1. Potential mechanisms by which the microbiota
affects CNS function
Altered microbial composition. Exogenously administered potential
probiotic bacteria or infectious agents can affect the composition of
the gut microbiota in multiple ways [77]. For example, they can
compete for dietary ingredients, bioconvert sugars into fermentation products with inhibitory properties, produce growth substrates
for other bacteria, compete for binding sites on the enteric wall,
improve gut barrier function, reduce inflammation, and stimulate
innate immune responses.
Immune activation. Microbiota and probiotic agents can have
direct effects on the immune system [91]. The immune system also
exerts bidirectional communication with the CNS [92], making it a
prime target for transducing the effects of bacteria on the CNS. In
addition, indirect effects of the gut microbiota and probiotics on the
innate immune system can result in alterations in the circulating
levels of proinflammatory and anti-inflammatory cytokines that
directly affect brain function.
Neural pathways. The vagus nerve, the major nerve of the
parasympathetic division of the autonomic nervous system, regulates
several vital body functions [93,94]. Microbiota can elicit signals via
the vagal nerve to the brain and vice versa [95–97]. For example, the
behavioral effects mediated by two separate probiotic strains in
rodents were dependent on intact vagal nerve activation [98].
Tryptophan metabolism. Serotonin is a biogenic amine that
functions as a neurotransmitter in the body and depends on the
availability of its precursor, tryptophan. Dysregulation of the kynurenine arm of the tryptophan metabolic pathway is involved in many
disorders of both the brain and GI tract. This initial step in the
kynurenine cascade is catalyzed by either indoleamine-2,3-dioxygenase or the largely hepatic-based tryptophan 2,3-dioxygenase. The
activity of both enzymes can be induced by inflammatory mediators
and by corticosteroids [99]. There is some evidence to suggest that a
probiotic can alter concentrations of kynurenine [100].
Gut hormonal response. The gut communicates to the brain via
hormonal signaling pathways that involve the release of gut
peptides with modulatory functions from enteroendocrine cells
[101,102]. Studies in germ-free mice suggest that the gut microbiota
mediates and regulates the release of gut peptides [103].
Bacterial metabolites. Bacterial products or metabolites from gut
commensals, such as SCFAs, may translocate from the intestinal
mucosa to the systemic circulation, where they could interfere with
immune regulation and CNS function. SCFAs are produced via the
fermentation of dietary carbohydrates and have immunomodulatory properties [104]. SCFAs can interact with nerve cells by
stimulating the sympathetic nervous system [105].
The aim of this review is to juxtapose the parallel early
development of the intestinal microbiota and the nervous
system taking into account environmental and maternal
influences that can affect microbe to brain signaling and
thus behavior throughout life.
Developmental windows: gut microbiota and
neurodevelopment
The prenatal and postnatal periods in mammalian development are critical developmental windows that are characterized by rapid changes in neuronal and microbial
organization. During these periods environmental factors
could have a long-term impact on brain and behavior,
resulting in brain disorders (Figure 2). Brain development
requires a delicate and complex balance of genetic and
environmental factors both during prenatal and postnatal
periods. Disruption of these elements can alter developmental trajectories and may lead to the onset of neurodevelopmental and other brain disorders later in life [19–21].
Recently, several preclinical studies using germ-free mice
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highlighted the ability of early life microbiota to influence
neurodevelopment, with long-lasting effects on neural function [17,22,112]. During development, the nervous system is
assembled and sculpted by a series of temporally regulated
developmental processes that shape the functional neural
circuitry that is critical for normal cognitive, motor, and
emotional development. This is a complex process consisting
of an orchestrated series of neurodevelopmental events
including, but not limited to, neurogenesis (the birth of
new neurons), axonal and dendritic growth, synaptogenesis,
and refinement of these synaptic connections, which generate the required numbers of neurons and the appropriate
synaptic density to match the requirements of the neural
circuit they become part of, a process known as ‘systems
matching’ [23,24]. These processes begin in utero and are
later refined and modified during early postnatal development. Disturbance during these processes can have profound structural and functional consequences for brain
development in affected offspring [19–21,25].
Prenatal period
Microbiota development
Despite a common dogma that the intrauterine environment and fetus are sterile until delivery, some evidence
demostrates bacterial presence in the intrauterine environment, suggesting that these bacteria may influence the
microbiota of the infant before birth [26–30]. The presence
of bacterial species in the fetus (such as Escherichia coli,
Enterococcus faecium, and Staphylococcus epidermidis)
could result from the translocation of the mother’s gut
bacteria via the bloodstream and placenta [28]. Specifically, Enterococcus, Streptococcus, Staphylococcus, and Propionibacterium species have been isolated from umbilical
cord blood, suggesting the potential for translocation. Further support of this notion comes from the animal study
demonstrating that E. faecium strains orally fed to the
dams were later detected in the amniotic fluid [31]. Lactobacillus and Bifidobacterium DNA were detected in the
placenta of vaginally and cesarean section delivered
infants, without cultivation of any viable cells, suggesting
translocation form the mother’s gut, (Figure 3) [29]. More
recently the presence of a defined placenta microbiome has
been identified with a signature similar to that in the
mother’s oral cavity. The functional role of this microbiome
on the developing brain now needs to be characterized [32].
Establishment of pioneer gut microbiota is a crucial stage
in neonatal development, overlapping with this critical
period of brain development [33] (Figure 4).
Brain development
The first major neurodevelopmental event critical to normal
brain development is formation of the neural tube, a process
event known as neurulation. In humans, this occurs by 3–4
weeks of gestation [25,34,35], following which cortical neurogenesis occurs predominantly during in utero gestation,
but can continue up to 2.5 years of age [25,36], outside the
neurogenic niches that persist in defined areas of the postnatal brain. Furthermore, hippocampal neurogenesis peaks
around 8–9 weeks and this can persist well into the postnatal period [25,37,38]. Gliogenesis (the development of glial
cells) also begins during the in utero period and mature
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Box 2. Leaky gut: at the core of brain–gut axis disorders?
The intestinal epithelium, the largest mucosal surface in the human
body, provides an interface between the environment and the host,
and is a key element in maintaining the equilibrium and overall
health of the organism. In a healthy state, the intestinal epithelium
and its associated tight-junction proteins (these include occludin,
junctional adhesion molecule, and claudin family members that
interact with cytoplasmic linker proteins such as zonula occludens1) together with the mucus layer act as a physical barrier to bacteria
and foreign antigens.
Under certain pathological conditions such as infections or stress,
the integrity of the epithelial barrier is compromised and it becomes
leaky, allowing for the translocation of pathobionts (pathological
bacteria) across the mucosal lining to sites where direct interaction
with immune cells and the enteric nervous system can occur [106].
This leads to activation of an immune response characterized by
increased production of peripheral proinflammatory mediators and
eventually the CNS (Figure 1).
Leaky gut or impaired intestinal permeability has been linked not
only to the GI dysfunction but also to psychiatric disorders, such as
depression and chronic fatigue syndrome [107–109]. For example,
patients with major depression have been found to show increased
peripheral blood antibody titers to lipopolysaccharides derived from
Gram-negative enterobacteria as compared with normal volunteers
[108]. Microbial-based strategies that enhance barrier function may
be useful for such disorders. Indeed, in preclinical studies, administration of probiotics such as Lactobacillus farciminis, Bacteroides
fragilis, and Lactobacillus salivarius can reverse the leakiness
induced by acute stress, maternal infection, and hydrogen peroxide,
respectively [86,110,111]. It is currently unclear whether the
intestinal permeability is a cause or consequence of such brain
disorders and future research efforts in this regard will be important
for the field. Nonetheless, a better understanding of the role and the
mechanisms of a leaky gut in the pathogenesis of brain–gut axis
disorders will allow the advent of novel therapies aimed at reestablishing appropriate intestinal barrier function.
astrocytes are present in the brain by 15 weeks of gestation.
Although these vary in density in different anatomical
locations, they continue to differentiate throughout the fetal
stage and well into the postnatal period [39]. This peak
period of gliogenesis coincides with a large increase in
neuronal complexity through elaboration of the dendritic
fields [40], coupled with a robust increase in synaptogenesis
only after astrocytes appear within the brain [41], suggesting mechanisms exist to ensure that appropriate neuronal–
glial interactions are established.
Importantly, the developing brain has been shown to be
susceptible to both internal and external environmental
cues during prenatal life. Maternal diet, infection, prenatal
stress, and microbial pathogen infections during the prenatal period have been associated with neurodevelopmental
disorders such as autism, attention deficit hyperactivity
disorder (ADHD), and schizophrenia [42–45]. Experimental
studies in rodents provide further support for this notion,
demonstrating that exposure to microbial pathogens during
similar developmental periods results in behavioral abnormalities, including anxiety-like behavior and impaired
cognitive function [42,46,47]. Maternal health plays a key
role in microbiota development and neurodevelopment [48],
therefore characterizing the composition of the microbiota
during pregnancy and its contribution to the development of
the newborn’s microbiota, and potentially brain development is an important step in developing microbiota-modulating interventions (Figure 3).
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Postnatal period
Microbiota development
During and shortly after birth, infants are exposed to
microbes mainly originating from the mother. Growing
evidence suggests that it is the inoculation and subsequent development of the intestinal microbiota in early
life that is crucial for healthy development, especially
neurodevelopment. The most dramatic changes in the
composition of the intestinal microbiota take place postnatally. A plethora of factors influence the composition of
the infant gut microbiota and potential functional outcomes (Figure 4). The initial microbial gut colonization is
dependent on the birth delivery mode. Whereas vaginally
born infants are colonized by fecal and vaginal bacteria
from the mother, infants born by cesarean delivery are
exposed to a different bacterial milieu closely related to
that of the human skin and hospital environment [33,49].
Although reasons for these correlations are difficult to
tease apart, it has been linked to the crucial role of the
early life environment in the development of a healthy
microbiome. Infants delivered by cesarean delivery are
more likely to suffer from allergies, asthma, GI dysfunction, obesity, and diabetes later in life [50], yet it is
currently unclear if it is the actual birth mode or the
medical indication for this intervention that most influences brain development and behavior.
In addition to the birth delivery mode, gestational age
is thought to contribute to the microbial composition of
the host. For example, the microbiota of preterm infants
lacks two of the main bacterial genera usually present in
full-term infants [51]. Breastfeeding, however, enriches
the microbiota of preterm infants with the missing microbial species, enhancing the ability of the infant microbiome to utilize human milk oligosaccharides [52]. In
addition to the maternal role in the developing infant’s
microbiome [53], genetic and environmental factors play
a role in defining the adult core microbiome. For example,
twin studies revealed higher similarities in the microbiota composition between monozygotic and dizygotic
twins in comparison to other family members, suggesting
a significance of environmental factors over genetics
[54,55], and that microbial ecologies tend to cluster in
family members [56]. The contribution of genetic background and environmental factors to the microbiota of
the host and subsequent functional outcomes remain to
be fully elucidated. During the first days of life, gut
microbiota of the infant is of low diversity and unstable,
and stabilizes during breast or formula feeding. The
precise composition of the developing microbiota population is dependent on whether the infant is breast or
formula fed [57]. The microbiota of the formula-fed infants
appears to be more diverse than breastfed infants, whose
microbiota has a more stable colonized pattern [58,113,114].
However, breastfed infants demonstrate better neurodevelopmental outcomes and higher scores on intelligence tests
[59], but whether these neurodevelopmental outcomes are a
reflection of the microbiota composition remains to be elucidated. The next great changes in the composition of the
intestinal microbiota come with the introduction of solid food
and weaning, since diet plays a crucial role in modulating
microbiota composition.
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(Years)
(Weeks)
32
23
40
2
12
18
20+
Old age
Microbiota stability
Prenatal
Infancy
Childhood
Adolesence
Adulthood + old age
Neuronal complexity through the lifespan
Synapc density
Stages of brain development
Age of onset of mental disorders
ADHD
Neuronal migraon
Axonal and dendric growth
Programmed cell death
Synaptogenesis
Ausm
Schizophrenia
Anxiety disorders
Mood disorders
Impulse-control disorders
Myelinaon
Process modeling/synapc refinement
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Figure 2. Temporal profile of neurodevelopmental sequences in relation to the age of onset of mental disorders and degree of microbiota stability/diversity throughout life.
Gut microbiota is essential to human health and is a key player in the bidirectional communication between the gastrointestinal tract and the central nervous system. The
microbiota dynamically changes throughout lifespan, establishing its symbiotic rapport with the host with critical windows during infancy, adolescence, and aging. During
these windows, the organism is vulnerable to external stressors, which may result in mental disorders. Early life perturbations of the developing gut microbiota can impact
neurodevelopment and potentially lead to adverse mental health outcomes later in life. The concept of parallel and interacting microbial–neural critical windows opens new
avenues for developing novel microbiota-modulating based therapeutic interventions in early life to combat neurodevelopmental deficits and brain disorders.
Abbreviation: ADHD, attention deficit hyperactivity disorder.
Neurodevelopment
The postnatal period is critical for brain development. For
most vertebrates, the majority of organ and tissue development occurs during embryogenesis, and postnatal
changes are primarily concerned with growth. However,
the CNS is different in that a considerable amount of
morphological development, cell differentiation, and acquisition of function takes place during postnatal development. Synaptogenesis begins in earnest in the human
brain after approximately post-birth (after the appearance
of astrocytes) and synaptic density increases rapidly after
birth to reach maximum levels by approximately 2 years of
age, at which point there are 50% more synapses than are
found in the adult brain [36,60,61]. After this stage, the
brain undergoes a process of synaptic refinement and
elimination to reduce the number of synapses in a region-specific manner to adult levels by mid-adolescence
[60,62,63]. Recent evidence demonstrates that developmental cortical remodeling, including the substantial elimination of synapses, continues well beyond adolescence and
throughout the third decade of life, before stabilizing at
adult levels [61]. This process of synaptic remodeling is not
accompanied by any major neuronal loss, suggesting that
this process of refinement reflects a strengthening and
consolidation of newly formed neural circuits during
childhood, which continues well into adulthood. This is
an extraordinarily protracted phase of developmental
reorganization, which may reflect the extended phase of
the development of cognitive abilities and the behavioral
transition from developmental mode to adult status in
humans [61]. What is clear is that this has profound
implications for our understanding of how environmental
exposures at specific stages of the lifespan may impact
neural plasticity to modify neurobehavioral development,
and what implications this may have for the risk of neurodevelopmental and neuropsychiatric disorders.
Childhood and adolescence period
Microbiota development
The gut microbiota, following initial colonization during
infancy and birth, continues to develop throughout childhood and adolescence. Gradual changes in microbiota
composition occur during early childhood, with a general
reduction in the number of aerobes and facultative anaerobes and an increase in the populations of anaerobic
species [64]. Although it is generally assumed that children’s gut microbiota resembles that of an adult [65],
recent studies demonstrate a less diverse microbiota with
sufficiently different microbial gut communities in adolescent children in comparison to adults [66–68]. Furthermore, adolescence is associated with hormonal changes
and fluctuations; however, not much is known about the
effects of puberty and hormonal changes on microbiota
development. It is currently unclear whether hormonal
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Prenatal
Infancy and childhood
Dietary, pre-probioc
supplementaon
Dietary,
pre-probioc
supplementaon
Diet
formula
Breaseeding
Maternal
microbiota
Maternal
microbiota
?
?
Placenta
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Figure 3. Windows of opportunity to modulate the microbiome of the infant prenatally and postnatally. Microbiota–gut–brain communication during prenatal and postnatal
development is shown. Although still controversial, some evidence suggests that the microbiota of the infant before birth is not sterile, but may be influenced by the
maternal immune state and nutrition. Prenatal and postnatal development undergoes vigorous neurodevelopmental phases and it is possible that it may be indirectly
influenced by the fetal microbial population (via microbiota of the mother). This opens avenues for the development of novel dietary and microbe-modulating therapies,
which may directly and indirectly alter the composition of the microbiota and neurodevelopment of the infant.
changes during adolescence have differential effects on the
microbiota of females and males that may result in differential susceptibility of men and women to various disorders. For example, autism and schizophrenia have a higher
occurrence in males [69], whereas mood disorders and
inflammatory bowel syndrome are more prevalent in
females [70,71]. Outstanding questions regarding the functional consequences of microbiota dysbiosis during this
critical time period will be important challenges to be
addressed in coming years.
It appears that instability and immaturity of gut microbiota during childhood and adolescence could be susceptible to environmental insults, such as the use of antibiotics,
stress, harmful environment, poor diet, and infection,
which could result in dysbiosis and potentially have a
negative impact on general and mental health, leading
to development of brain disorders later in life.
Neurodevelopment
Importantly, similar to gut microbiota development, brain
maturation undergoes a crucial developmental phase during childhood and adolescence. The adolescence period is
considered the most critical for development and onset of
various brain disorders (Figure 2) [72]. Early adolescence is
a key stage during neurodevelopment with various structural, neurochemical, and molecular changes occurring in
response to genetic and environmental signals [72]. These
include synaptic pruning, where the elimination of the
6
extra synapses occurs, resulting in decreased levels of
cortical gray matter as the brain matures. Coinciding with
this is the formation of new neuronal connections producing a phase of high plasticity throughout much of the brain.
A consequence of this major neuronal rewiring during
adolescence is a high level of vulnerability to pathological
insults ranging from stress to drugs, to abuse, and to
dietary deficiencies [72]. This developmental period is also
the peak time for the onset of numerous psychiatric disorders including schizophrenia, substance abuse, and
mood disorders [72] (Figure 2). Thus, the vulnerability of
the adolescent brain to pathological insult in combination
with instability and immaturity of gut microbiota during
adolescence makes the brain exceptionally susceptible to
aberrant changes that forecast the onset of brain disorders
during this time period.
Adulthood and aging
As adulthood approaches, the gut microbiota stabilizes and
becomes more diverse [65]. The adult gut microbiota is
individual-specific and remains relatively stable over time
[65], and can resist detrimental environmental elements
such as use of antibiotics and stress by restoring its diverse
and stable ‘normal’ core microbiota [73]. However, it is
worth noting that recent evidence challenges the idea of
the gut microbiota as stable during adulthood [74], suggesting that gut microbes can be rapidly altered by shortterm changes in diet. At this point it is unclear whether
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Mode of nutrional provision
Breastfeeding
Mode of delivery
Cesarean
Vaginal
Diet
formula
V
Pre-probioc
supplement
Genecs
Gestaonal age
Hospitalizaon
Maternal infecon
Maternal disease
Maternal stress
Environmental
Anbiocs
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Figure 4. Factors influencing the development of the infant microbiota. Several factors play a role in shaping of the bacterial landscape in the development of the infant
microbiota. In addition to mode of birth, mode of early nutrition, environment, other factors such as gestational age, genetics, and hospitalization, also influence the
microbial composition of the infant. Infections (both maternal and infant) and antibiotic usage influence the trajectory of the developing microbiota as does the selective
transient enrichment by probiotics and prebiotics. Taken together, such a plethora of factors with the ability to modulate the microbiota development suggest the
importance of environmental influence superimposed over genetics in the establishment of a core microbiome.
CNS health could also be rapidly affected by such changes.
Similar to the maturation and stabilization of the gut
microbiota, continuous brain maturation occurs during
this period of adulthood.
Regressive (e.g., synaptic pruning) and progressive (e.g.,
myelination) cellular events continue to occur in adulthood. Although the brain reaches its maximal weight by
approximately 20 years of age [75], white matter volume
continues to increase up until approximately the mid-forties [76], which coincides with the peak of myelination
observed at approximately 50 years of age [76]. Although
adulthood does not appear to be a critical or vulnerable
phase, it remains a period during which alterations in the
microbiota can influence brain and behavior. Therefore,
maintaining a healthy gut microbiota and mental health is
an important aspect in possible prevention or attenuation
brain disorders associated with aging.
Although the aging period is not part of the neurodevelopmental category, it is still a critical window for both
CNS and gut function. Aging can have a detrimental effect
on the composition of the gut microbiota, which in turn
might influence health outcomes at this stage of life [77].
The gut microbiome evolves throughout the lifespan, but
microbiota diversity and stability decline with aging
[78,79]. It has recently been shown that the microbial
composition of aged individuals correlated with, and was
influenced by, their residential community, dietary regimen, and health status of the individual [80]. In addition to
a range of medications used by the elderly, impaired
digestive and motility functions, and thus malabsorption
of nutrients, and a weakened immune system contribute to
compromised diversity and stability of the gut microbiota
composition [77,79,81]. Decreased stability and diversity of
the gut microbiota in the elderly is accompanied by reduced
7
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Review
brain volume and cognitive function. Indeed, brain weight
begins to decline around approximately 55 years of age
[75]. Volumetric imaging studies in aging populations have
shown gray and white matter volume loss in an age-dependent manner, with peak loss occurring in most dorsal
brain regions between the ages of 50 and 70 with a more
gradual decline thereafter [82,83]. These age-associated
changes in brain morphology are in parallel with the
disrupted immune system, increased oxidative stress,
and accumulation of amyloid plaques in the brain, all of
which are reflected in weakened cognitive and behavioral
function, and may manifest in various age-related memory
impairments and disorders such as Alzheimer’s disease.
Interestingly, findings from the ELDERMET (http://
eldermet.ucc.ie) research consortium focused on prospectively characterizing the gut microbiota of elderly subjects,
suggest the importance of nutrition on microbiota composition in the elderly [80]. These findings prompt the notion
of modulating the microbiota of the elderly by dietary/
microbiota-modifying interventions to restore microbiota
diversity and thus improve general and possibly mental
health, especially in such a critical window as aging.
Brain disorders and the microbiota–gut–brain axis:
autism and beyond
Maternal infection and stress during pregnancy have been
shown to increase the risk for neurodevelopmental disorders
such as schizophrenia and autism in offspring (or distinct
cognitive and behavioral pathological symptoms in later life).
This association appears to be critically dependent on the
precise prenatal timing of the insult. Neurodevelopmental
disorders are characterized by impaired brain development
and behavioral, cognitive, and/or physical abnormalities.
Several share behavioral abnormalities in sociability, communication, and/or compulsive activity. Autism spectrum
disorders (ASDs) are neurodevelopmental disorders characterized by the presence of stereotypical behavior, communication, and social interaction deficits [84]. Although ASD
etiology remains unknown, genetic and environmental factors are thought to play a role in its etiopathogenesis [85]. GI
abnormalities associated with ASDs have been linked to
alterations in microbiota composition and function [18,86–
89]. Despite these correlational studies, clinical data interpretation is compromised by high rates of antibiotic use and
marked dietary variations in ASD patients, which makes it
difficult to draw definite conclusions about ASD-related
microbiota changes [4]. Studies in germ-free mice demonstrated robust and reproducible social deficits and increases
in repetitive behaviors similar to that observed in ASD [90],
suggesting that the microbiota is a critical factor in the
development of social behavior and the etiology of ASDs.
Most recently, studies demonstrated that autism-like behavioral and GI phenotypes are associated with altered microbiota in two separate mouse models of ASDs [18,86]. Both
clinical and preclinical studies provide promising evidence
indicating an important role for the gut microbiota in the
pathogenesis of ASDs, creating opportunities for developing
novel therapeutic strategies in managing neurodevelopmental disorders via microbiome-based treatment. Indeed, Bacteroides fragilis given in early adolescence has been shown to
ameliorate some, but not all, of the behavioral dysfunctions in
8
Trends in Molecular Medicine xxx xxxx, Vol. xxx, No. x
Box 3. Outstanding questions
Does the microbiota during adolescence play a role in brain
function and behavior?
What are the underlying mechanisms as to how bacteria in the gut
signal to the brain? Does it change across the lifespan?
What is the reason for sex-specific effects in neurodevelopment
and microbiota development and their consequences?
Can microbiota-based therapies be used in humans for treating
mental disorders?
a mouse model of autism [86]. Moreover, whether other
neurodevelopmental disorders such as schizophrenia and
ADHD are associated with microbiota changes remains to
be investigated either in animal models or human populations, and such studies are now warranted.
Concluding remarks and future perspectives
It is becoming clear that perturbations in microbiota can
contribute to neurodevelopmental and psychiatric disorders
onset later in life. Knowing that the microbiota can significantly interfere with the human cognitive and immune
systems, the initiation of symbiosis, especially during prenatal, early postnatal, and adolescence phases appears to be
a crucial step for optimizing brain development overall and
mental health later in life. Although there seem to be critical
windows in neurological and microbiota development, the
underlying mechanisms of these effects remain to be elucidated (Box 3). Unraveling the mechanisms that trigger
these sequelae will improve our knowledge of the etiology
of neurodevelopmental psychiatric disorders, enable identification of biomarkers of dysfunction, and allow the identification of new windows of opportunity for the development
of novel therapeutic interventions.
In conclusion, the concept of parallel and interacting
microbial–neural critical windows opens new avenues for
developing novel microbiota-modulating based therapeutic
strategies in early life to combat neurodevelopmental deficits and brain disorders. Unlike a genetic background, the
gut microbiota may be modified in throughout life and
possibly pregnancy. Early preweaning and adolescence
periods appear to be critical periods for modifying enteric
microbiota with the potential to prevent the development
of abnormal behaviors. Consequently, it is becoming clear
that understanding the early interaction between the intestinal microbiota and the host opens novel avenues for
nutritional/therapeutic interventions in at-risk populations, particularly for infants and young children.
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